99O_PR – KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non–Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation

G.J. Riely1, S-H.I. Ou2, I. Rybkin3, A. Spira4, K. Papadopoulos5, J.K. Sabari6, M. Johnson7, R.S. Heist8, L. Bazhenova9, M. Barve10, J.M. Pacheco11, K. Velastegui12, C. Cilliers12, P. Olson12, J.G. Christensen12, T. Kheoh12, R.C. Chao12, P.A. Jänne13
1Thoracic Oncology Service, Division of Solid Tumor, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA, 2University of California Irvine, Orange, AL, USA, 3Henry Ford Cancer Institute, Henry Ford Hospital, Detroit, USA, 4Research Institute, Virginia Cancer Specialist, Fairfax, USA, 5Clinical Research department, South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA, 6Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA, 7Lung Cancer Research, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA, 8Massachusetts General Hospital, Boston, MA, USA, 9Medicine, Moores Cancer Center – UC San Diego Health, La Jolla, CA, USA, 10Mary Crowley Cancer Research, Dallas, TX, USA, 11Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 12Mirati Therapeutics, Inc., San Diego, CA, USA, 13Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA

Background: KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (~24 h), and extensive tissue distribution.

Methods: KRYSTAL-1 (NCT03785249) is a multi-cohort phase I/II study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRASG12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.

Results: As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14). Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n=3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.

Conclusions: Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRASG12C-mutant NSCLC. Additional PD and mechanistic data will be presented.

Clinical trial identification: NCT03785249
Editorial acknowledgement: Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.
Legal entity responsible for the study: Mirati Therapeutics, Inc.
Funding: Mirati Therapeutics, Inc.

Discolsure: G.J. Riely: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda ; Advisory/Consultancy: Mirati Therapeutics. S-H.I. Ou: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: TP Therapeutics; Speaker Bureau/Expert testimony: Genentech; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Takeda; Shareholder/Stockholder/Stock options: Turning Point Therapeutics.
I. Rybkin: Advisory/Consultancy: AstraZeneca. A. Spira: Shareholder/Stockholder/Stock options: Lilly; Advisory/Consultancy: Incyte; Advisory/Consultancy: Amgen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Gritstone ; Advisory/Consultancy: Jazz Pharmaceuticals; Honoraria (self): CytomX Therapeutics; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Amgen; Honoraria (self): Janssen Oncology; Honoraria (self): Novartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Bayer. K. Papadopoulos: Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Basilea. M. Johnson: Spouse/Financial dependant: Otsuka; Travel/Accommodation/Expenses: Abbvie; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Incyte; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Sanofi. R.S. Heist: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Tarveda; Advisory/Consultancy: Apollonia; Honoraria (self): Chugai/Roche. L. Bazhenova: Shareholder/Stockholder/Stock options: Epic Sciences; Advisory/Consultancy, Research grant/Funding (self): Beyond Spring Pharmaceuticals; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: G1; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Merck; Advisory/Consultancy: Johnson & Johnson; Advisory/Consultancy: BMSi; Advisory/Consultancy: Daichi Sankyo; Advisory/Consultancy: Neuvogen. J.M. Pacheco: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Gerson Lehrman; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Takeda. K. Velastegui: Full/Part-time employment: Mirati Therapeutics, Inc. C. Cilliers: Full/Part-time employment: Mirati Therapeutics, Inc. P. Olson: Full/Part-time employment: Mirati Therapeutics, Inc. J.G. Christensen: Leadership role, Shareholder/Stockholder/Stock options, Officer/Board of Directors: Mirati Therapeutics, Inc; Advisory/Consultancy: BridgeBio; Leadership role, Shareholder/Stockholder/Stock options: BCTG Acquisition; Shareholder/Stockholder/Stock options: Bluebird Bio. T. Kheoh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc; Shareholder/Stockholder/Stock options: Tocagen. R.C. Chao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc. P.A. Jänne: Shareholder/Stockholder/Stock options: Gatekeeper Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo; Research grant/Funding (self): Revolution Medicines; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Daichi Sankyo; Research grant/Funding (self): Astellas; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Chugai; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Araxes; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Silicon Therapeutics. All other authors have declared no conflicts of interest.